Barhl2 limits growth of the diencephalic primordium through Caspase3 inhibition of β-catenin activation
Barhl2 limits growth of the diencephalic primordium through Caspase3 inhibition of β-catenin activation
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DOI：
10.1073/pnas.1014017108
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发表时间：
2011-02-08
影响因子：
11.1
通讯作者：
Durand, Beatrice C.
中科院分区：
文献类型：
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作者：
Juraver-Geslin, Hugo A.;Ausseil, Jerome J.;Durand, Beatrice C.
关于细胞增殖和细胞死亡在控制脊椎动物前脑生长中的作用，我们知之甚少。同源域蛋白Barhl2在非洲爪哇、斑马鱼和小鼠胚胎的间脑中都有表达，我们之前的研究表明，在非洲爪哇神经上皮细胞中过表达Barhl2可以诱导依赖于Caspase3的细胞凋亡。在这里，通过Caspase3的非传统功能，barhl2被显示为间脑增殖的刹车。Barhl2或Caspase3的缺失会导致间脑细胞数量的增加，神经上皮结构的破坏，以及Wnt活性的增加。令人惊讶的是，这些变化并不是由细胞凋亡减少引起的，而是由于β-连环素的数量和激活增加，从而刺激神经上皮细胞过度增殖，导致细胞内定位缺陷，以及β-连环素/T细胞因子/淋巴增强因子信号转导的两个下游靶点Axin2和Cylind1上调。通过两组不同的互补实验，我们发现，在发育中的间脑中，Caspase3作用于Barhl2下游，通过抑制β-连环蛋白的激活来限制神经上皮细胞的增殖。我们的数据认为，Bar同源域蛋白作为Caspase3活性的细胞类型特异性调节因子具有保守的功能。
Little is known about the respective contributions of cell proliferation and cell death to the control of vertebrate fore-brain growth. The homeodomain protein barhl2 is expressed in the diencephalons of Xenopus, zebrafish, and mouse embryos, and we previously showed that Barhl2 overexpression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. Here, barhl2 is shown to act as a brake on diencephalic proliferation through an unconventional function of Caspase3. Depletion of Barhl2 or Caspase3 causes an increase in diencephalic cell number, a disruption of the neuroepithelium architecture, and an increase in Wnt activity. Surprisingly, these changes are not caused by decreased apoptosis but instead, are because of an increase in the amount and activation of beta-catenin, which stimulates excessive neuroepithelial cell proliferation and induces defects in beta-catenin intracellular localization and an up-regulation of axin2 and cyclinD1, two downstream targets of beta-catenin/T-cell factor/lymphoid enhancer factor signaling. Using two different sets of complementation experiments, we showed that, in the developing diencephalon, Caspase3 acts downstream of Barhl2 in limiting neuroepithelial cell proliferation by inhibiting beta-catenin activation. Our data argue that Bar homeodomain proteins share a conserved function as cell type-specific regulators of Caspase3 activities.